Maternal Exposure to Prostaglandin E2 Affects Hippocampal Synaptic Plasticity in Mice Offspring -A Link to Autism Spectrum Disorder

Prostaglandin E2 (PGE2) is a lipid signaling molecule involved in early healthy brain development. Exposure to environmental risk factors such as air pollutants, infections, and drugs such as acetaminophen during early pregnancy have shown to impact PGE2 levels and have all been linked to Autism Spectrum Disorders (ASDs). Our previous studies show that maternal exposure to PGE2 and the lack of the PGE2 producing enzyme Cyclooxygenase-2 (COX2) results in sex-specific abnormal dendritic morphology within the cerebellum and the hippocampus as well as ASD-like behaviors including motor deficits and anxiety in mice offspring. In this study, I investigated sex-dependent effects of prenatal PGE2 exposure on hippocampal electrophysiology in the C57bl/6 mice offspring at postnatal day 90-100. I measured Schaffer collateral long-term potentiation (LTP), paired-pulse facilitation (PPF), input/output (I/O) responses, the expression of glutamate receptor components NMDAR subunit 2A, AMPA subunit GluR1, beta-actin, and morphological characteristics such as primary dendrite length and cell soma size of pyramidal neurons in the hippocampus. I found that PGE2 exposure decreased LTP in males and I/O responses in females at higher stimulation intensities with no effect on PPF. PGE2 also increased the expression of NMDAR2A in males with no effect on GluR1 or β-actin. However, PGE2 did not affect pyramidal cell morphology. Overall, our data suggests that prenatal PGE2 exposure disrupts innate sex differences by reducing LTP maintenance in males, while impairing basal synaptic strength in females. I propose a model that PGE2-dependent upregulation of NMDAR2A observed in male offspring may reflect a
neurotoxicity effect of PGE2 mediated by glutamate, subsequently leading to neuronal death, which could explain the corresponding decrease in LTP. In summary, this study adds further evidence that abnormal maternal PGE2 levels known to be influenced by many environmental risk factors may affect hippocampal function and contribute to specific deficits in ASDs in a sex-dependent manner.